The LH receptor (LHR) and FSH receptor (FSHR), collectively termed the gonadotropin receptors, are GPCRs that play a pivotal role in reproductive physiology. Recent studies from our laboratory and others suggest that the LHR self-associates into high molecular weight complexes consistent with dimers and oligomers of the receptor. The focus of this grant is to mechanistically and functionally examine the dimerization/oligomerization of the hLHR as well as the closely related hFSHR. In spite of the growing body of evidence that GPCRs exist as dimers/oligomers, the region(s) of a given GPCR mediating dimerization appear varied and the functional role(s) of the dimers/oligomers remains enigmatic. We propose to utilize novel and complementary approaches to address these questions as they relate to gonadotropin receptor dimerization/oligomerization. In addition, given the precedence for hetero-dimerization/oligomerization between different GPCRs, the high degree of homology between the hLHR and hFSHR, and the expression of both the hLHR and hFSHR in differentiated granulosa cells, a particularly relevant question we will also address is whether the hLHR and hFSHR form hetero-dimers/oligomers and what the functional ramifications of this are. The specific aims of the grant, therefore, are to: (1) determine the functional role(s) of cell surface gonadotropin receptor dimerization; (2) determine if the hLHR and hFSHR hetero-dimerize and, if so, examine the functional consequences of this phenomenon; and (3) determine the structural region(s) mediating homo- and hetero-dimerization of the gonadotropin receptors. Overall, the proposed studies in the grant will contribute novel and significant insights into homo- and heterodimerization/oligomerization of the gonadotropin receptors, providing new paradigms for the roles of these receptors in reproductive endocrinology.